Genetic Variant ATL2:p.Pro548Ser (chr2-38296104-G-A) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_001135673.4(ATL2):c.1642C>T(p.Pro548Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000265 in 1,398,318 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

ATL2
NM_001135673.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.57

Variant links:

Genes affected

ATL2 (HGNC:24047): (atlastin GTPase 2) Enables identical protein binding activity. Involved in Golgi organization; endoplasmic reticulum tubular network membrane organization; and protein homooligomerization. Located in endoplasmic reticulum tubular network membrane. Is integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ATL2 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.41640127).

BS2

High AC in GnomAdExome4 at 37 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATL2	NM_001135673.4 link	c.1642C>T	p.Pro548Ser	missense_variant	Exon 13 of 13	ENST00000378954.9	NP_001129145.1	Q8NHH9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATL2	ENST00000378954.9 link	c.1642C>T	p.Pro548Ser	missense_variant	Exon 13 of 13	1	NM_001135673.4	ENSP00000368237.4		Q8NHH9-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.000115

AC:

AN:

155930

Hom.:

AF XY:

0.0000848

AC XY:

AN XY:

82554

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000751

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000228

GnomAD4 exome

AF:

0.0000265

AC:

AN:

1398318

Hom.:

Cov.:

AF XY:

0.0000304

AC XY:

AN XY:

689678

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000442

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000345

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000735

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1642C>T (p.P548S) alteration is located in exon 13 (coding exon 13) of the ATL2 gene. This alteration results from a C to T substitution at nucleotide position 1642, causing the proline (P) at amino acid position 548 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Uncertain

0.047

BayesDel_noAF

Pathogenic

0.20

CADD

Uncertain

DANN

Benign

0.96

DEOGEN2

Benign

0.14

T;.;.

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.88

D;D;D

M_CAP

Benign

0.065

MetaRNN

Benign

0.42

T;T;T

MetaSVM

Uncertain

0.21

MutationAssessor

Uncertain

2.7

M;.;.

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-3.4

D;D;D

REVEL

Uncertain

0.63

Sift

Benign

0.10

T;T;T

Sift4G

Benign

0.072

T;T;T

Polyphen

0.064

B;.;.

Vest4

0.65

MutPred

0.52

Loss of catalytic residue at Q544 (P = 0.0991);.;.;

MVP

0.88

MPC

0.15

ClinPred

0.30

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.29

gMVP

0.73

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over